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Biomedical subjects

M Vranic

Publications and source records attributed to M Vranic.

At least 163 records · Page 9Linked to original sources
PubMed1978

Experimental validation of measurements of glucose turnover in nonsteady state.

The aim of the present experiments is to validate, in conscious dogs, the tracer infusion methods of measuring nonsteady turnover rates. This was done in nine experiments performed in four normal dogs by infusing isotopically labeled glucose (2-3H, 6-3H, 1-14C) and monitoring the concentrations of both the labeled and unlabeled substances. The validation is based on the observation that a high exogenous infusion of glucose will suppress endogenous glucose production and become the sole source of glucose in the body. By infusing glucose at a high, time-varying rate, calculating its rate of appearance, (Ra) and comparing it to the infused rate, the method can be verified. The calculations were based on: a) a single-compartment model with a modified volume of distribution; b) a two-compartment model; and c) a generalized dispersion model. The absolute values of the areas of the deviations of the calculated from the infused curves were found to be, respectively, 9.5, 8.4, and 7.8 percent of the total area under the infused curve. It was concluded that the tracer infusion method can reliably measure Ra of glucose when it is changing rapidly, and the system is out of steady state.

Animals↗
PubMed1978

Extrapancreatic glucagon in control of glucose turnover in depancreatized dogs.

Depancreatized dogs have plasma immunoreactive glucagon (IRG), which is of gastric origin and is immunologically indistinguishable from pancreatic glucagon. The effects of extrapancreatic IRG on the tracer-determined rate of glucose production were examined to establish whether this hormone contributes to the hyperglycemia observed in six conscious, depancreatized dogs after insulin withdrawal. The dogs were initially maintained normoglycemic with an intraportal insulin infusion. Insulin withdrawal resulted in a 53 and 70% decrease of serum immunoreactive insulin (IRI) at 60 and 210 min, respectively. At 60 min, plasma glucose rose and Ra increased by 50%. A somatostatin-induced decrease in IRG prevented a further increase in Ra and glucose; after somatostatin withdrawal, IRG, Ra, and plasma glucose increased. Arginine given 1 or 3 h after insulin withdrawal increased IRG by 100 pg/ml, and mean Ra rose by 8.9 mg/kg-min. Thus, in depancreatized dogs with low but detectable serum IRI, IRG suppression is associated with inhibition of Ra and further rise in plasma glucose is prevented. Stimulation of IRG release increases Ra and results in marked hyperglycemia. It is concluded that extrapancreatic glucagon has a diabetogenic effect during acute insulin defiency.

Animals↗
PubMed1978

Extrapancreatic glucagon and glucagonlike immunoreactivity in depancreatized dogs. A quantitative assessment of secretion rates and anatomical delineation of sources.

The anatomical sites and the rates of extrapancreatic secretion of glucagon and of glucagon-like immunoreactivity (GLI) were assessed in dogs 2 h after pancreatectomy by catheterization of the gastrosplenic and mesenteric veins. Glucagon release from the gastrosplenic area approximated one-fourth that of a normal pancreas and rose from 0.25 to 1.0 ng/kg per min during arginine stimulation. Intestinal glucagon secretion was small and did not respond to arginine, suggesting that the stomach is the only important extrapancreatic source of glucagon. Glucagon concentrations attained by gastrosplenic secretion were in close proportion to those obtained during the administration of exogenous glucagon, indicating similar clearance rates of extrapancreatic and pancreatic glucagon, approximating 10 ml/kg per min.GLI secretion (0.3 ng eq/kg per min) was limited to the intestinal area and was transiently stimulated by arginine and exogenous glucagon. Base-line GLI clearance approximated 1 ml/kg per min. No insulin secretion could be detected. Gastrointestinal glucose uptake rose from 0.56 to 2.2 mg/kg per min after glucagon administration suggesting that as much as 10% of total glucose production can be taken up by the gastrointestinal tract. In two dogs both the stomach and pancreas were removed. Intestinal glucagon release remained small and did not increase during arginine administration. By contrast, GLI release was stimulated by both arginine and exogenous glucagon.

Animals↗
PubMed1977

Studies of glucose turnover and renal function in an unusual case of hereditary fructose intolerance.

Examination of glucose kinetics, pancreatic alpha and beta cell function, plasma lipids, urinary acidification and calcium excretion has been undertaken in a patient with hereditary fructose intolerance. This case was unusual as it was associated with insulin-requiring diabetes, type IV hyperlipemia, hypercalciuria and renal calculi. He also demonstrated the previously described fructose-induced defect of urine acidification. Glucagon and C-peptide assays showed that the pancreatic alpha cells were stimulated by fructose and that the beta cells did not respond to fructose. It is not known whether the latter was due to his diabetes or to the lack of a beta cell response to this sugar. Primed 14C-glucose infusions were used for the first time to study nonsteady state glucose kinetics in man. They showed that, 24 hours after the last insulin injection and under basal conditions, the glucose concentrations increased because glucose production exceeded glucose utilization. However, after the administration of sorbitol the plasma glucose concentration decreased because glucose production decreased. After the administration of sorbitol there was no change in the metabolic clearance of glucose. This reflects the lack of a peripheral insulin effect and is consistent with the lack of any measurable C-peptide. Glucose utilization also decreased, but this decrease was less than the decrease in glucose production. Because the metabolic clearance of glucose remained unchanged, it was concluded that the change in glucose utilization was solely due to the decrease in glucose concentration. The absence of C-peptide in the plasma indicated that changes in glucose turnover were not related to any changes in endogenous plasma insulin. Furthermore, the plasma glucagon concentration increased and, hence, changes in this hormone could not account for the decrease in glucose production. Therefore, it was concluded that the sorbitol-induced decline in glucose production was due to a direct effect on hepatic metabolism.

Administration, Oral↗
PubMed1977

Turnover and recycling of glucose in man during prolonged fasting.

The effect of prolonged (3-5 wk) fasting on tracer-determined glucose turnover and of recycling radioactive glucose has been examined. We followed the specific activity of plasma glucose after the simultaneous administration of 1-14C-glucose and 3-3H-glucose. The rate of glucose turnover decreased during prolonged fasting. Recycling of radioactive glucose was estimated by two different techniques: (1) the appearance of 14C in positions 2 to 6 glucose was measured; (2) the difference in the slopes of specific activity decline for 1-14C-glucose and for 3-3H-glucose was calculated. The two methods of estimating the radioactive recycling gave results similar to each other. The amount of glucose recycled did not change during prolonged fasting. However, in view of the decline in glucose production during fasting, the proportion of glucose production which was represented by recycling increased. Based on weight and urinary nitrogen loss an estimate of the glucose production from amino acids and glycerol was obtained. The difference between the rate of glucose production from the contribution of amino acids and glycerol and that estimated by radioisotopic techniques was much larger than the measured rate of recycling. This finding suggests that either a large exchange of 12C with 14C occurred in some glycolytic intermediates or that a hitherto unknown source of carbon for glucose production appeared during prolonged fasting.

Adult↗
PubMed1977

Endocrine cells in oxyntic mucosa of a dog 5 years after pancreatectomy.

Immunofluorescence shows that the oxyntic mucosa of a dog depancreatized for 5 years and having a poorly-controlled diabetes has more glucagon- and somatostatin-containing cells than the mucosa of a control dog. At the ultrastructural level, 4 endocrine cell types are identified: A-, A-like, D- and enterochromaffin-like (ECL) cells, with increased numbers of A-, A-like and D-cells in gastric glands of the depancreatized dog, together with a higher concentration of immunoreactive glucagon in the gastric mucosa. The increase in A-, A-like and D-cells is compatible with: a) a change induced by the diabetic state itself; b) a hyperplasia secondary to the loss of corresponding pancreatic cells. At any rate, the fact that A-, A-like and D-cells increase parallely may indicate that these three cell types are functionally related one with another.

Animals↗
PubMed1977

Mechanism of exercise-induced hypoglycemia in depancreatized dogs maintained on long-acting insulin.

Human diabetics on intermediate and long-acting insulin occasionaly become hypoglycemic during exercise. We have shown previously that during exercise, hypoglycemia did not occur in depancreatized insulin-infused dogs because the increments in glucose production and utilization were proportional and of the same magnitude as in normal dogs. Therefore, to elucidate the mechanism of the glucose-lowering effect of strenuous exercise, we measured glucose production and utilization, metabolic clearance of glucose, and serum immunoreactive insulin in postabsorptive depancreatized dogs 8 h after a subcutaneous injection of protamine zinc and crystalline insulin. During rest, plasma glucose was stable, but ranged between hypoglycemia and hyperglycemia. Hyperglycemia was associated with overproduction of glucose, indicating insulin deficiency despite normal or elevated serum immunoreactive insulin. Glucose clearance, as in normal dogs, increased threefold but glucose production increased only marginally (50%) and, consequently, glucose decreased in plasma. The decrease of plasma glucose was directly proportional to the preexercise concentration and production of glucose. The magnitude of inhibition glucose production was not correlated with the serum immunoreactive insulin indicating either that some released insluin was not active or that a moderate immunoreactive insulin increment induced a near-maximal inhibition. It is concluded that in depancreatized dogs injected with protamine zinc insulin, exercise accelerates mobilization of insulin from its injection site presumably because of increased blood and lymph flow. Glucose utilization did not exceed that in normal dogs, but hepatic glucose production failed to increase sufficiently to meet the needs of muscle in exercise.

Animals↗
PubMed1977

The effect of a peripheral decarboxylase inhibitor (carbidopa) on monoamine and neuroendocrine function in man.

Carbidopa, a selective extracerebral decarboxylase inhibitor, was given to 10 normal volunteers to determine its effects on endogenous catecholamine, indoleamine, and endocrine function. Tryptamine, which is largely extracerebral in origin, was inhibited markedly (80 percent) by the carbidopa; 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenolglycol (MHPG) excretion also were inhibited by the drug but not to the same degree as tryptamine. These differential results may be due partly to the higher central nervous system origin of the 5-HIAA and MHPG but also to a peripheral "stores" effect. In addition, carbidopa resulted in significant increases in plasma prolactin and a small but significant decrease in plasma glucagon.

Adult↗
PubMed1977

Estimating rapid changes in the rates of glucose production from glycogenolysis and recycling through lactate.

In order to obtain independent estimates of changes in the rate of glucose production from glycogenolysis from the glucose carbon recycled throught lactate, previously validated nonsteady tracer methods are used. Changes in glycogenolysis are estimated by calculating the rate of appearance of a label ([6-3H]glucose) uniformly distributed through glycogen and simultaneously the rate of recycling of 14C is measured under nonsteady-state conditions. It is indicated that these results can be extended to the determination of absolute rates of glucose production from glycogen breakdown and gluconeogenetic precursors.

Animals↗
PubMed1976

Plasma glucagon in pups, decreased by fasting, unaffected by somatostatin or hypoglycemia.

In pups less than 4 days old, the mean basal plasma immunoreactive glucagon (IRG) level was about 3 times higher than in adult dogs. This high level decreased with age, and in pups older than 12 days the mean plasma IRG level did not differ from that in adults. Insulin-induced hypoglycemia did not raise plasma IRG concentration in young pups. Fasting decreased plasma IRG in young, but not in older pups. This decrease is consistent with the decrease in gluconeogenesis and in contrast to the metabolic adjustments observed in the adult organism. In pups less than 7 days old, both the pancreas and gastric mucosa contained considerably more IRG than the normal value reported for adult dogs. Gastroduodenal IRG was immunologically indistinguishable from pancreatic glucagon. In pups, somatostatin did not decrease the plasma concentration of either IRG or immunoreactive insulin (IRI) and caused no change in plasma glucose or in the rates of glucose production and utilization calculated from experiments with tracers. The experiments indicate that in pups the pancreatic and gastric alpha-cells are unresponsive to stimuli normally effective in grown dogs.

Age Factors↗
PubMed1976

The essentiality of insulin and the role of glucagon in regulating glucose utilization and production during strenuous exercise in dogs.

UNLABELLED: In order to elucidate the role of insulin and glucagon during strenuous exercise (100 m/min, slope 10-12 degrees), we have determined the rates of production (Ra), utilization (Rd), and metabolic clearance (M) of glucose in normal dogs before pancreatectomy and 2 wk after total pancreatectomy (a) when they were being maintained on constant intraportal basal insulin infusion, (245 muU/kg-min) and (b) when insulin supply had been withheld before and during exercise. Such an intense exercise induced in normal dogs a prompt decrease in mean immunoreactive serum insulin (IRI) from 20 +/- 3 to 11 +/- 2 muU/ml. In depancreatized insulin-infused dogs serum IRI during rest and exercise was between 14 +/- 1 and 12 +/- 2 muU/ml. In the third group, after cessation of insulin infusion, IRI decreased by 76% (from 17 +/- 5 to 4 +/- 1) and did not decrease futher during exercise. During exercise, serum immunoreactive glucagon (IRG) increased threefold in normal dogs. In depancreatized dogs serum IRG was the same as in normal resting dogs (indicating a nonpancreatic source of the hormone) but it did not increase during exercise. In normal dogs exercise induced proportional increases in Ra, Rd, and M (threefold) and normoglycemia was maintained. Changes in glucose turnover in depancreatized insulin-infused dogs were similar to those seen in normal dogs suggesting that a decrease in insulin secretion and a rise in IRG are not essential to prevent hypoglycemia in diabetic dogs. With the cessation of insulin infusion in resting depancreatized dogs, Ra increased, M decreased, and hyperglycemia ensued. During exercise, Ra continued to rise, but M did not increase significantly. CONCLUSIONS: (a) Regulation of glucose production by liver during exercise is multifactorial. A decrease in IRI and an increase in IRG are not the only factors which can promote delivery of glucose to the peripheral tissues. The insulin glucagon molar ratio was found not to be an essential metabolic functional unit in regulating glucose metabolism during exercise. (b) It is hypothesized that increases in blood flow and capillary surface area can lead to an increase in the amount of insulin delivered to the muscle even when serum levels of IRI are reduced during exercies. It is suggested that small, but adequate amounts of insulin (as found in normal and depancreatized insulin-infused dogs) are essential in regulating glucose uptake in the working muscle. (c) Since totally depancreatized dogs had normal serum levels of IRG (originating presumably from the gastrointestinal tract), the question of essentiality of basal glucagon activity in glucose homeostasis during exercise could not be resolved by these experiments. It appears, however, that regulation of secretion of nonpancreatic glucagon differs from that of pancreatic glucagon.

Animals↗
PubMed1976

Measurement and partial characterization of immunoreactive glucagon in gastrointestinal tissues of dogs.

We have reported previously that increasing amounts of immunoreactive glucagon (IRG), measured by four specific antisera, appeared in plasma of depancreatized insulin-deficient dogs. It was therefore concluded that pancreatectomy was not accompanied by glucagon deficiency in the dog, but instead excessive amounts of extrapancreatic IRG could contribute to the diabetic syndrome. In order to locate the source of extrapancreatic glucagon, tissue extracts were assayed with anti-glucagon sera 30-K and K-44, which cross-react minimally with crude gut extracts. IRG was detected in all gastrointestinal tissues and in the salivary glands, but not in extracts of liver, kidney, brain, heart atrium, and adenohypophysis. Immunologic dilution curves of extracts from all gastrointestinal tissues were parallel to those of the pure pancreatic glucagon standard, and both antisera (30-K and K-44) measured the same concentrations. The highest concentration of gastrointestinal IRG was found in the fundus and corpus of the stomach. Presence of IRG in gastrointestinal tissues of depancreatized dogs indicates that gastrointestinal cells can not only secrete but also store large amounts of IRG. Extracts of mucosa of stomach fundus were further purified by gel filtration on Biogel P-30 columns. The immunoreactivity in the eluate was assayed by 30-K and a strongly crossreacting antibody, K-4023. One pooled fraction corresponding to marker pancreatic glucagon in its elution volume was found to contain the largest amount of IRG and the highest specific immunoreactivity (IRG/protein concentration). This fraction showed also the highest activity in a glucagon-receptor assay system. Disc gel electrophoresis in the presence of urea resolved this fraction into three immunoreactive components, one of which was identical to pancreatic glucagon in its electrophoretic mobility. It appears, therefore, that mucosa of the upper stomach in the dog contains a polypeptide similar to pancreatic glucagon. We conclude that (a) hyperglucagonemia in the dog can result from excessive secretion of IRG not only by the pancreatic alpha cells but also by cells of the gastrointestinal tract; (b) the highest IRG concentration was found in fundus and corpus of the stomach and lower concentrations throughout the gastrointestinal tract; (c) the IRG component in the stomach displayed immunologic and physical properties similar to pancreatic glucagon.

Animals↗
PubMed1975

The role of insulin and glucagon in regulating glucose turnover in dogs during exercise.

During exercise the flux of glucose is regulated so that the increased demand of glucose by the muscle is met by a corresponding increased release of glucose by the liver; plasma glucose concentration does not change markedly, while glucose turnover increases. These precise regulatory mechanisms can be studied by quantitative isotope dilution methods; measurements of plasma glucose concentrations do not necessarily reflect any changes in glucose fluxes. Insulin is considered to be an important regulatory hormone during exercise. Its concentration decreases during exercise in part because of a decrease in insulin secretion by the pancreas and in part because the removal of insulin is increased. This conclusion was reached because insulin concentration in plasma decreased both in normal and in depancreatized insulin-infused dogs. A sudden decrease of portal insulin concentration facilitates glycogenolysis and gluconeogenesis in the liver. At the same time blood flow decreases in those areas which are inactive during exercise such as the splanchnic beds, while increased blood flow and opening of the capillary beds increases the total amount of insulin perfusing the muscle. Therefore, even in presence of low insulin concentration in plasma the insulin supply to the working muscle can presumably be maintained at an adequate level. We considered that exercise changes the distribution of insulin in relation to the liver and the muscle; such a distribution pattern may represent an important physiological regulatory mechanism. The question whether glucagon is essential in regulating glucose production during exercise could not be resolved because depancreatized insulin-infused dogs had essentially normal plasma concentrations of immunoreactive glucagon. Glucagon concentration increases during strenuous but not during moderate exercise of normal dogs. This increase is apparently not indispensable because during strenuous exercise depancreatized insulin-infused dogs did not increase IRG

Animals↗
PubMed1975

Turnover of plasma oleic acid measured by radio-gas chromatography.

Gas-liquid chromatography with radioactivity detection (Radio-GLC) was investigated as an analytical means of determining the fractional turnover rates of plasma free fatty acids. For this purpose normal dogs were infused with 1.838 muCi/min of [1-14C]oleic acid complexed with albumin and plasma samples were taken at 0 to 110 minutes. The plasma free fatty acids were isolated by a modified Dole extraction and the methyl esters, prepared by diazomethylation, were identified and quantitated by GLC and radio-GLC using radioactive methyl heptadecanoate as internal standard. The study demonstrates that physiologically feasible infusion rates and loads of radioactive acids can be found which permit accurate analyses of plasma free fatty acids by radio-GLC. During a 2-hour infusion no labeled acid other than oleic appeared in plasma indicating that the method could be used to study the turnover of a mixture of fatty acids simultaneously. These results also indicate that conventional methods of determination of radioactivity in purified extracts can be employed without concern for recycling of label among the fatty acids, at least over short periods of time. The radio-GLC technique described yields approximately 20% higher fractional turnover times for oleic acid than do standard methods.

Animals↗